Autoimmunity is an attack on the host carried out by its own immune system. Genetic and environmental agents, i.e., infectious agents, are thought to be major contributing factors in both the induction of autoimmunity and in precipitation of relapse events. Significant attention has been given to possible mechanisms of autoimmune activation following infection. However, little is understood concerning the mechanisms that prevent autoimmunity, especially following an infection that produces pathology similar or identical to an autoimmune disease. In this proposal we will use a viral infection of the central nervous system (CNS) that induces significant demyelination, a hallmark of human multiple sclerosis (MS) and murine experimental autoimmune encephalitis (EAE), without progressing to autoimmunity. The virus used is the glial tropic JHM strain of mouse hepatitis virus (JHMV). This infection of the murine CNS produces a nonfatal encephalomyelitis. The host's immune system clears infectious virus from the CNS but is unable to affect sterile immunity, resulting in a persistence viral infection confined to the CNS. Demyelination is a hallmark finding associated with both the acute infection and, importantly, the persistent infection. Following viral induced demyelination autoreactive T cells are not present during the window of maximal demyelination, but only during viral persistence, after resolution of the infection and re-established blood brain barrier integrity. Nevertheless there is no evidence of an autoimmune response associated with these self reactive T cells. This proposal examines the mechanisms regulating both the induction and suppression of autoreactive T cells. Our overall hypothesis is that extensive viral induced demyelination following acute infection induces a milieu within the CNS which suppresses the effector function of self reactive T cells. This proposal defines the kinetics of activation and CNS retention of self reactive T cells secreting interferon gamma (IFN-?) interleukin (IL)-17, and IL-9 and defines the requirement for demyelination in the activation of self reactive T cells. The concept that suppression of self reactivity is a residual effect of acute viral encephalomyelitis is tested by adoptive transfer of encephalitogenic Th1, Th9 and Th17 cells into persistently infected mice. Finally a novel transgenic mouse which allows depletion of regulatory T cells within the CNS during viral persistence will prove that regulatory T cells prevent expression of self reactive T cell effector function. Using both virus specific reagents and tools developed to understand EAE regulation these data will provide a mechanistic understanding of the regulation self reactive T cells induced by a viral infection. In addition, the data will provide the first demonstration of a viral induced mechanism suppressing effector function specifically within the target tissue, preventing autoimmune attack by self reactive T cells.